Boehringer Ingelheim Pharmaceuticals, Inc. Release: Long-Term Data Presented At American Heart Association Scientific Sessions Reinforce Safety Profile Of Pradaxa® (dabigatran etexilate mesylate)

RIDGEFIELD, Conn., Nov. 18, 2013 /PRNewswire/ -- Boehringer Ingelheim Pharmaceuticals, Inc. today announced results from a new, long-term, combined analysis of the pivotal Phase III RE-LY® trial and its extension safety study RELY-ABLE®. The data showed that after a median follow up of 4.6 years, with some patients followed up to 6.7 years, rates of stroke/systemic embolism and major bleeding were consistent with rates in previously reported analyses of RE-LY, one of the largest stroke prevention clinical studies ever conducted in patients with non-valvular atrial fibrillation (NVAF). The results were presented today during the American Heart Association's Scientific Sessions 2013.

"This is the first set of data to provide results after long-term continuous follow-up of more than four years in a large set of NVAF patients who were treated with one of the newer oral anticoagulants (OAC)," said Michael D. Ezekowitz, M.D., Ph.D., FACC, professor of medicine at Thomas Jefferson Medical College in Philadelphia. "Patients with NVAF need long-term treatment with anticoagulants in order to lower their risk of stroke, and these data are crucial in understanding PRADAXA's long-term safety in patients with NVAF."

Following the RE-LY trial, a total of 5,851 patients, who were randomized to either 110 mg* or 150 mg twice daily (BID) of dabigatran, continued the same blinded dose of dabigatran in RELY-ABLE. Median follow up was 4.6 years, with a maximum 6.7 years total follow up (RE-LY plus RELY-ABLE). This new analysis showed that the rates of stroke or systemic embolism for dabigatran 150 mg BID and 110 mg BID were 1.25 percent and 1.54 percent per year, respectively. The low rates of hemorrhagic stroke seen during RE-LY (approximately one case per thousand per year) were observed over the whole duration of follow-up. Mortality rates were similar for the two dabigatran doses: 3.43 percent per year for 150 mg BID and 3.55 percent per year for 110 mg BID; HR 0.97 (95% CI: 0.87-1.08). Additional results from the combined analysis of RE-LY and RELY-ABLE included:

• Rates of ischemic stroke for dabigatran 150 mg BID and 110 mg BID: 1.03 percent and 1.29 percent per year, respectively
• Rates of major hemorrhage for dabigatran 150 mg BID and 110 mg BID: 3.34 percent and 2.76 percent per year, respectively

"We are pleased that these long-term results are consistent with our pivotal RE-LY data and support PRADAXA 150 mg twice daily as an important treatment option in patients with NVAF when used as directed," said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, U.S. Regional Medical Director, Boehringer Ingelheim Pharmaceuticals, Inc. "Boehringer Ingelheim was the leader in bringing the first novel oral anticoagulant treatment to patients with NVAF to reduce the risk of stroke. We are proud to present these results from the only study showing this length of follow-up."

PRADAXA was the first OAC approved by the U.S. Food and Drug Administration in more than 50 years to reduce the risk of stroke and systemic embolism in patients with NVAF. PRADAXA is the only OAC to be shown to be superior to warfarin in reducing ischemic stroke, a key consideration in anticoagulant therapy given that nearly nine out of 10 strokes caused by atrial fibrillation (AFib) are ischemic strokes. Since its discovery 20 years ago, PRADAXA has been evaluated through the extensive RE-VOLUTION® clinical trial program, which includes 10 completed clinical trials involving approximately 40,000 patients in more than 44 countries.

About RE-LY®
The efficacy and safety of PRADAXA was established in the RE-LY trial, one of the largest stroke prevention clinical studies ever conducted in patients with NVAF. RE-LY was a global, Phase III, randomized trial of 18,113 patients enrolled in 951 centers in 44 countries, investigating whether dabigatran etexilate (two blinded doses) was as effective as open label warfarin INR 2.0 - 3.0 for stroke prevention. Patients with NVAF and at least one other risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack, or systemic embolism, left ventricular ejection fraction <40 percent, symptomatic heart failure, New York Heart Association Class > 2, age > 75 years, age > 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension) were enrolled in the study for two years with a minimum follow-up period of one year.

The RE-LY trial utilized the established PROBE (prospective, randomized, open-label, blinded endpoint evaluation) clinical trial protocol, which has been used in previous trials of anticoagulation for stroke prevention in patients with AFib. A PROBE design may reflect the differences in the management of warfarin and dabigatran in clinical practice.

The primary endpoint of the trial was incidence of stroke (including ischemic and hemorrhagic) and systemic embolism. The primary safety endpoint was major bleeding, defined as a reduction in the hemoglobin level of at least 2.0 g/dL, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. Other safety endpoints included bleeding events (major and minor), intracerebral hemorrhage, other intracranial hemorrhage, liver function and other adverse events.

In RE-LY, PRADAXA 150mg twice daily significantly reduced the risk of stroke and systemic embolism by 35 percent more than warfarin (based on incidences of 2.2 percent for PRADAXA 150mg vs. 3.4 percent for warfarin), with a similar rate of major bleeding events. PRADAXA 150mg twice daily also showed a 59 percent lower rate of intracranial bleeding and a superior 25 percent reduction of ischemic stroke in the RE-LY trial, compared to warfarin.

In the RE-LY trial, all clinical outcomes were adjudicated in a blinded manner to assess outcomes for each treatment.

About RELY-ABLE®
RELY-ABLE was a global, extension trial of 5,851 dabigatran-treated patients across 35 countries who continued on from the 12,091 patients in the original RE-LY study.

There were some limitations to the RELY-ABLE trial. About half of the patients originally enrolled in RE-LY subsequently enrolled in RELY-ABLE. Patients were eligible if they did not prematurely discontinue PRADAXA therapy. Also, it was at the investigator's discretion to determine if it was clinically appropriate for patients to continue receiving long-term OAC treatment. Patients randomized to warfarin (n=6,022) in RE-LY were not eligible for RELY-ABLE.

Also, there was no event adjudication, meaning confirmation by an independent team or group, in RELY-ABLE, whereas there was event adjudication in RE-LY. Lastly, patients enrolled in RELY-ABLE had different baseline characteristics from those in RE-LY and may have been at lower risk of events.

*Although studied in the RE-LY and RELY-ABLE trials, dabigatran 110mg is not approved by the U.S. FDA.

About Pradaxa® (dabigatran etexilate mesylate) Capsules

Indications and Usage

Pradaxa® (dabigatran etexilate mesylate) capsules is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

CONTRAINDICATIONS
PRADAXA is contraindicated in patients with:

• active pathological bleeding;
• known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA;
• mechanical prosthetic heart valve

WARNINGS & PRECAUTIONS
Increased Risk of Stroke with Discontinuation of PRADAXA
Discontinuing PRADAXA in absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

Risk of Bleeding

• PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
• Risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA's anticoagulant activity and half-life are increased in patients with renal impairment.
• A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Activated prothrombin complex concentrates, recombinant Factor VIIa, or concentrates of factors II, IX or X may be considered but their use has not been evaluated. Protamine sulfate and vitamin K are not expected to affect dabigatran anticoagulant activity. Consider administration of platelet concentrates where thrombocytopenia is present or long-acting antiplatelet drugs have been used.

Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
The safety and efficacy of PRADAXA in patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than 3 months prior to enrollment) was evaluated in the phase 2 RE-ALIGN trial. RE-ALIGN was terminated early because of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) for PRADAXA vs warfarin. Therefore, the use of PRADAXA is contraindicated in patients with mechanical prosthetic valves.

Use of PRADAXA for the prophylaxis of thromboembolic events in patients with AFib in the setting of other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are major independent factors in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.

• For patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA.
• For patients with severe renal impairment (CrCl 15-30 mL/min), avoid concomitant use of PRADAXA and P-gp inhibitors.

ADVERSE REACTIONS
In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal (GI) events.

• PRADAXA 150 mg resulted in higher rates of major GI bleeds and any GI bleeds compared to warfarin.
• In patients >75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin.
• Patients on PRADAXA 150 mg had an increased incidence of GI adverse reactions.
• These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer). Drug hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA.

Other Measures Evaluated
In the pivotal trial, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

Please see full Prescribing Information including Boxed WARNING, and Medication Guide.

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About Boehringer Ingelheim Pharmaceuticals, Inc.
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The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

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PRADAXA® is a registered trademark of Boehringer Ingelheim Pharma GmBH and Co. KG and used under license.

RE-LY® and RELY-ABLE® are registered service marks of Boehringer Ingelheim International GmBH and used under license.

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